Genetics: Understanding Chromosome Disorders

Chromosomal abnormalities, in the form of aneuploidy, are very common among humans. Roughly 8 percent of all conceptions are aneuploid, and it's estimated that up to half of all miscarriages are due to some form of chromosome disorder. Sex chromosome disorders are the most commonly observed type of aneuploidy in humans, because X-chromosome inactivation allows individuals with more than two X chromosomes to compensate for the extra "doses" and survive the condition.

Four common categories of aneuploidy crop up in humans:

Nullisomy: Occurs when a chromosome is missing altogether. Generally, embryos that are nullisomic don't survive to be born.

Monosomy: Occurs when one chromosome lacks its homolog.

Trisomy: Occurs when one extra copy of a chromosome is present.

Tetrasomy: Occurs when four total copies of a chromosome are present. Tetrasomy is extremely rare.

Most chromosome conditions are referred to by category of aneuploidy followed by the number of the affected chromosome. For example, trisomy 13 means that three copies of chromosome 13 are present.

When chromosomes are left out

Monosomy (when one chromosome lacks its homolog) in humans is very rare. The majority of embryos with monosomies don't survive to be born. For liveborn infants, the only autosomal monosomy reported in humans is monosomy 21. Signs and symptoms of monosomy 21 are similar to those of Down syndrome. Infants with monosomy 21 often have numerous birth defects and rarely survive for longer than a few days or weeks. The other monosomy commonly seen in children is monosomy of the X chromosome. Children with this condition are always female and usually lead normal lives. Both monosomy 21 and monosomy 13 are the result of nondisjunction during meiosis.

Many monosomies are partial losses of chromosomes, meaning that part (or all) of the missing chromosome is attached to another chromosome. Movements of parts of chromosomes to other, nonhomologous chromosomes are the result of translocations.

Finally, monosomies can occur in cells as a result of mistakes that occur during cell division (mitosis). Many of these monosomies are associated with chemical exposure and various sorts of cancers.

When too many chromosomes are left in

Trisomies (when one extra copy of a chromosome is present) are the most common sorts of chromosomal abnormalities observed in humans. The most common trisomy is Down syndrome, or trisomy 21. Other less common trisomies include trisomy 18 (Edward syndrome), trisomy 13 (Patau syndrome), and trisomy 8. All these trisomies are usually the result of nondisjunction during meiosis.

Down syndrome

Trisomy of chromosome 21, commonly called Down syndrome, affects between 1 in 600 to 1 in 800 infants. People with Down syndrome have some rather stereotyped physical characteristics, including distinct facial features, altered body shape, and short stature. Individuals with Down syndrome are usually mentally retarded and often have heart defects. Nevertheless, they often lead fulfilling and active lives well into adulthood.

One of the most striking features of Down syndrome (and trisomies, in general) is the precipitous increase in the number of Down syndrome babies born to mothers over 35 years of age. Women between the ages of 18 and 25 have a very low risk of having a baby with trisomy 21 (roughly 1 in 2,000). The risk increases slightly but steadily for women between the ages of 25 and 35 (about 1 in 900 for women 30 years old) and then jumps dramatically. By the time a woman is 40 years old, the probability of having a child with Down syndrome is one in 100. By the age of 50, the probability of conceiving a Down syndrome child is 1 in 12. Why does the risk of Down syndrome increase in the children of older women?

The majority of Down syndrome cases seem to arise from nondisjunction during meiosis. The reason behind this failure of chromosomes to segregate normally in older women is unclear. In females, meiosis actually begins in the fetus. All developing eggs go through the first round of prophase, including recombination. Meiosis in future egg cells then stops in a stage called diplotene, the stage of crossing-over where homologous chromosomes are hooked together and are in the process of exchanging parts of their DNA. Meiosis doesn't start back up again until a particular developing egg is going through the process of ovulation. At that point, the egg completes the first round of meiosis and then halts again. When sperm and egg unite, the nucleus of the egg cell finishes meiosis just before the nuclei of the sperm and egg fuse to complete the process of fertilization. (In human males, meiosis begins in puberty, is ongoing and continues without pauses like those that occur in females.)

Roughly 75 percent of the nondisjunctions responsible for Down syndrome occur during the first phase of meiosis. Oddly, most of the chromosomes that fail to segregate seem also to have failed to undergo crossing-over, suggesting that the events leading up to nondisjunction begin early in life. Scientists have proposed a number of explanations for the cause of nondisjunction and its associated lack of crossing-over, but no agreement has been reached about what actually happens in the cell to prevent the chromosomes from segregating properly.

Every pregnancy is an independent genetic event. So although age is a factor in calculating risk of trisomy 21, Down syndrome with previous pregnancies doesn't necessarily increase a woman's risk of having another child affected by the disorder.

Some environmental factors have been implicated in Down syndrome that may increase the risk for younger women (less than 30 years of age). Scientists think that women who smoke while on oral contraceptives (birth control pills) may have a higher risk of decreased blood flow to their ovaries. When egg cells are starved for oxygen, they're less likely to develop normally, and nondisjunction may be more likely to occur.

Familial Down syndrome

A second form of Down syndrome, Familial Down syndrome, is unrelated to maternal age. This disorder occurs as a result of the fusion of chromosome 21 to another autosome (often chromosome 14). This fusion is usually the result of a translocation, what happens when non-homologous chromosomes exchange parts. In this case, the exchange involves the long arm of chromosome 21 and the short arm of chromosome 14. This sort of translocation is called a Robertsonian translocation. The leftover parts of chromosomes 14 and 21 also fuse together but are usually lost to cell division and aren't inherited. When a Robertsonian translocation occurs, affected persons can end up with several sorts of chromosome combinations in their gametes.

For Familial Down syndrome, a translocation carrier has one normal copy of chromosome 21, one normal copy of chromosome 14, and one fused translocation chromosome. Carriers aren't affected by Down syndrome because their fused chromosome acts as a second copy of the normal chromosome. When a carrier's cells undergo meiosis, some of their gametes have one translocated chromosome or get the normal complement that includes one copy of each chromosome. Fertilizations of gametes with a translocated chromosome produce the phenotype of Down syndrome. Roughly 10 percent of the liveborn children of carriers have trisomy 21. Carriers have a greater chance than normal of miscarriage due to monosomy (of either 21 or 14) and trisomy 14.